Biology subjects

Rahamim, N.

Publications and source records attributed to Rahamim, N..

3 recordsLinked to original sources

bioRxiv2023

Involvement of FKBP5, but not of stress, in alcohol memory reconsolidation

Relapse is a fundamental challenge in drug addiction, often evoked by exposure to drug-associated cues. Upon retrieval, memories become temporarily labile before re-stabilizing in a process termed reconsolidation. Therefore, targeting the reconsolidation process offers a therapeutic approach for relapse prevention via the disruption of the drug-cue memories. We recently demonstrated that retrieval of contextual alcohol memories increased the expression of the mRNA encoding for FK506 binding protein 51 (FKBP51), a regulator of the hypothalamic-pituitary-adrenal (HPA) axis. Here, we explored the role of the HPA axis, and FKBP5/FKBP51 in particular, in the reconsolidation of alcohol memories. We found that the FKBP51 inhibitor SAFit2 given before alcohol-memory retrieval using contextual cues prevented the extinction of alcohol place preference behavior in female mice, suggesting that this protein may play a role in cognitive flexibility in a sex-dependent manner. Conversely, the retrieval of alcohol memories using an odor-taste cue did not affect Fkbp5 expression in rats with a history of chronic alcohol consumption, suggesting that FKBP5 may play a differential role in different alcohol-associated memories. In addition, we provide evidence for HPA axis activation following alcohol memory retrieval, by showing that exposure to an alcohol-associated context led to elevated corticosterone secretion. However, we found that the reconsolidation process was unaffected by HPA axis-related manipulations, namely stress exposure, and administration of corticosterone or the glucocorticoid receptors inhibitor, mifepristone. Our results suggest that although FKBP5 can affect cognitive flexibility, and thereby impact the reconsolidation of alcohol memories, this effect is not likely mediated by HPA axis-related mechanisms.

neuroscience↗

bioRxiv2023

ERK1/2 inhibition disrupts alcohol memory reconsolidation and prevents relapse

Relapse to alcohol abuse after periods of abstinence, often caused by cue-induced alcohol craving, is a major challenge in the treatment of alcohol addiction. Therefore, disruption of the cue-alcohol associative memories can diminish the risk of relapse. Upon retrieval, memories become temporarily labile before they reconsolidate in a process that requires protein synthesis. Accumulating evidence suggests that the mammalian target of rapamycin complex 1 (mTORC1), which is responsible for the translation of a subset of dendritic proteins, is crucial for memory reconsolidation. Here, we explored the involvement of two regulatory pathways of mTORC1, namely phosphoinositide 3-kinase (PI3K)-AKT and extracellular regulated kinase1/2 (ERK1/2), in the reconsolidation process in a rat model of non-operant alcohol self-administration. We found that retrieval of alcohol memories using an odor-taste cue increased ERK1/2 activation in the amygdala, but did not affect the PI3K-AKT pathway. Importantly, inhibition of ERK1/2 shortly after alcohol memory retrieval impaired reconsolidation and led to long-lasting suppression of relapse to alcohol drinking. Additionally, we show that attenuation of alcohol memories and relapse was also induced by post-retrieval administration of lacosamide, an inhibitor of collapsin response mediator protein-2 (CRMP2) - a translational product of mTORC1 that is functionally regulated by PI3K-AKT signaling. Together, our findings provide evidence for the crucial role of ERK1/2 and CRMP2 in the reconsolidation of alcohol memories, and mark the FDA-approved drug, lacosamide, as a potential treatment for alcohol use disorder.

neuroscience↗

bioRxiv2023

Basal Ganglia Stimulation Ameliorates Schizophrenia Exploration Anomalies

Any learning agent must balance between exploiting its knowledge and exploring new alternatives. Schizophrenia patients are known to have maladaptive exploration-exploitation (E-E) balance1,2 and are impaired at reversal learning tasks as early as their first psychotic episode. The cortico-basal ganglia (BG)-dorsolateral prefrontal cortex (DLPFC) network plays a significant role in learning processes3,4. However, how this network maintains the E-E balance and what alters the balance in schizophrenia remains elusive. Using a combination of extracellular recordings, pharmacological manipulations, macro-stimulation techniques, and an adaptive reinforcement learning model, we show that in the non-human primate (NHP), the external segment of the globus pallidus (GPe, the central nucleus of the BG network) maintain this balance. Furthermore, whereas the chronic, low-dose administration of N-methyl-D-aspartate (NMDA) receptor (NMDA-R) antagonist, phencyclidine (PCP) leads to E-E imbalance, low-frequency GPe macro-stimulation restores it. E-E balance provides a holistic framework to resolve some of the apparent paradoxes that have emerged within schizophrenia research2. Our findings suggest that Schizophrenia symptoms may reflect abnormal DLPFC-BG E-E balance, and GPe stimulation may be advantageous for these patients.

neuroscience↗